22R-Hydroxycholesterol and 9-cis-Retinoic Acid Induce ATP-binding Cassette Transporter A1 Expression and Cholesterol Efflux in Brain Cells and Decrease Amyloid β Secretion
Open accessAbstract
The ATP-binding cassette transporter A1 (ABCA1) is a major regulator of peripheral cholesterol efflux and plasma high density lipoprotein metabolism. In adult rat brain we found high expression of ABCA1 in neurons in the hypothalamus, thalamus, amygdala, cholinergic basal forebrain, and hippocampus. Large neurons of the cholinergic nucleus basalis together with CA1 and CA3 pyramidal neurons were among the most abundantly immunolabeled neurons. Glia cells were largely negative. Because cholesterol homeostasis may have an essential role in central nervous system function and neurodegeneration, we examined ABCA1 expression and function in different brain cell types using cultures of primary neurons, astrocytes, and microglia isolated from embryonic rat brain. The basal ABCA1 mRNA and protein levels detected in these cell types were increased markedly after exposure to oxysterols and 9-cis-retinoic acid, which are ligands for the nuclear hormone liver X receptors and retinoic X receptors, respectively. Functionally, the increased ABCA1 expression caused by these ligands was followed by elevated apoA-I- and apoE-specific cholesterol efflux in neurons and glia. In non-neuronal and neuronal cells overexpressing a human Swedish variant of amyloid precursor protein, 22R-hydroxycholesterol and 9-cis-retinoic acid induced ABCA1 expression and increased apoA-I-mediated cholesterol efflux consequently decreasing cellular cholesterol content. More importantly, we demonstrated that these ligands alone or in combination with apoA-I caused a substantial reduction in the stability of amyloid precursor protein C-terminal fragments and decreased amyloid beta production. These effects of 22R-hydroxycholesterol may provide a novel strategy to decrease amyloid beta secretion and consequently reduce the amyloid burden in the brain.
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In vitro evidence supports a critical role of ABCA1 in Aβ production.
“Furthermore, several lines of in vitro evidence support the critical role of ABCA1 in A production, although how ABCA1 regulates A production remains to be clarified (Koldamova et al., 2003;Sun et al., 2003;Kim et al., 2007).”
From microRNA-33 Regulates ApoE Lipidation and Amyloid-β Metabolism in the Brain (2015) · cites this paper as Koldamova et al., 2003
The Abstract (page unavailable) reports decreased Aβ production in cultured cells after LXR/RXR ligand treatment, with or without ABCA1-mediated cholesterol depletion. The Discussion (page unavailable) says ABCA1 may affect APP processing and Aβ secretion, but also says the ligand effects might depend on factors beyond ABCA1. This supports a possible role, not the stronger claim that this study establishes a critical role for ABCA1. (LLM, conf=0.85)
Experimental — accuracy not yet measuredABCA1 induction decreases Aβ levels in cells by inhibiting both β- and γ-cleavage of APP.
“Koldamova et al. and Sun et al. reported that ABCA1 induction decreases Aβ levels in cells by inhibiting both β- and γ-cleavage of APP [62-64].”
From MicroRNAs in brain cholesterol metabolism and their implications for Alzheimer's disease (2016) · cites this paper as [62]
The APP-processing results report reduced Aβ secretion in cells treated with LXR/RXR ligands, alongside ABCA1 induction. They do not establish that ABCA1 induction inhibits both β- and γ-cleavage of APP; the paper says APP processing may also be affected through a mechanism independent of ABCA1-mediated cholesterol depletion. Section labels are available in our copy, but page numbers are not. (LLM, conf=0.88)
Experimental — accuracy not yet measuredABCA1 induction by LXR agonist decreases Aβ production in various cell lines.
“ABCA1 induction by liver X receptor (LXR) agonist decreased Aβ production in various cell lines (Kim et al., 2007; Koldamova et al., 2003; Sun et al., 2003).”
From miR-106b impairs cholesterol efflux and increases Aβ levels by repressing ABCA1 expression (2012) · cites this paper as Koldamova et al., 2003
The Abstract and the results on CHOAPPsw and H4APPsw cells report reduced Aβ secretion after LXR/RXR ligand treatment, alongside increased ABCA1 expression. The claim omits that the experiments used both LXR and RXR ligands and studied cells expressing mutant APP; the larger Aβ reductions were observed with added apoA-I. The paper does not establish that ABCA1 induction alone caused the decrease. (LLM, conf=0.85)
Experimental — accuracy not yet measuredMost studies demonstrated that ABCA1 induction decreases the levels of Aβ and CTFβ.
“Most of studies demonstrated that ABCA1 induction decreases the levels of Aβ and CTFβ (Kim et al., 2007; Koldamova et al., 2003; Sun et al., 2003).”
From miR-106b impairs cholesterol efflux and increases Aβ levels by repressing ABCA1 expression (2012) · cites this paper as Koldamova et al., 2003
In the Results section on APP processing (page unavailable), 22R and RA increased ABCA1 expression and reduced Aβ secretion and total APP C-terminal fragments in APPsw-expressing cells. The paper measures total CTF, not CTFβ specifically, and its Discussion says the effects on APP processing may involve factors beyond ABCA1-mediated cholesterol efflux. It therefore does not establish that ABCA1 induction itself decreases both Aβ and CTFβ. (LLM, conf=0.88)
Experimental — accuracy not yet measuredLXR agonists TO901317 and GW3965 alter Aβ production in neuronal and non-neuronal cell cultures overexpressing APP.
“It has been shown that the LXR agonists TO901317 and GW3965 alter amyloid- (A) production in neuronal and non-neuronal cell cultures overexpressing amyloid precursor protein (APP)”
From Critical Role of Astroglial Apolipoprotein E and Liver X Receptor-α Expression for Microglial Aβ Phagocytosis (2011) · cites this paper as Koldamova et al., 2003
The sections on APP processing and Aβ secretion in CHOAPPsw and H4APPsw cells report reduced Aβ secretion in non-neuronal and neuronal APP-overexpressing cultures. However, the treatments reported are 22R-hydroxycholesterol and 9-cis-retinoic acid, with apoA-I in the cited comparisons—not TO901317 or GW3965. Page numbers are unavailable in our copy. (LLM, conf=0.88)
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References 62 · Cited by 237
Research works printed but not linked: 8
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- Authors
- Koldamova, R. P., Lefterov, I. M., Ikonomovic, M. D., Skoko, J., Lefterov, P. I., Isanski, B. A., DeKosky, S. T., & Lazo, J. S.
- Affiliations
- University of Pittsburgh (US)
- Corresponding author
- Koldamova, Radosveta P.
- Lazo, John S.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2003-04
- Volume
- 278
- Issue
- 15
- Pages
- 13244-13256
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1487168219
- Cited by
- 237
- References
- 62
- Citations by year
- 2025: 4 · 2024: 6 · 2023: 6 · 2022: 7 · 2021: 9 · 2020: 10 · 2019: 4 · 2018: 5 · 2017: 5 · 2016: 6 · 2015: 12 · 2014: 14 · 2013: 10 · 2012: 12
- FWCI
- 20.28
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (AG 18558)
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- ABCA1, 22R-hydroxycholesterol, 9-cis-retinoic acid, cholesterol efflux, amyloid-beta secretion, amyloid precursor protein, oxysterols, liver X receptor, retinoid X receptor, apolipoprotein A-I, apolipoprotein E, brain neurons, astrocytes, microglia, cholesterol homeostasis, Alzheimer's disease, nuclear receptors
- MeSH terms
- Alitretinoin, Animals, Animals, Newborn, Brain, Cells, Cultured, Cerebral Cortex, Cholesterol, Embryo, Mammalian, Gene Expression Regulation, Hippocampus, Hydroxycholesterols, Kinetics, Ligands, Neurons, Organ Specificity, RNA, Messenger, Transcription, Genetic, Protein Biosynthesis, Tretinoin, Amyloid beta-Peptides, Rats, Sprague-Dawley, Microglia, Pyramidal Cells, ATP-Binding Cassette Transporters, Rats, ATP Binding Cassette Transporter 1
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